TY - JOUR TI - Kinase-dead ATM protein is highly oncogenic and can be preferentially targeted by Topo-isomerase I inhibitors AU - Yamamoto, Kenta AU - Wang, Jiguang AU - Sprinzen, Lisa AU - Xu, Jun AU - Haddock, Christopher J AU - Li, Chen AU - Lee, Brian J AU - Loredan, Denis G AU - Jiang, Wenxia AU - Vindigni, Alessandro AU - Wang, Dong AU - Rabadan, Raul AU - Zha, Shan A2 - Walter, Johannes VL - 5 PY - 2016 DA - 2016/06/15 SP - e14709 C1 - eLife 2016;5:e14709 DO - 10.7554/eLife.14709 UR - https://doi.org/10.7554/eLife.14709 AB - Missense mutations in ATM kinase, a master regulator of DNA damage responses, are found in many cancers, but their impact on ATM function and implications for cancer therapy are largely unknown. Here we report that 72% of cancer-associated ATM mutations are missense mutations that are enriched around the kinase domain. Expression of kinase-dead ATM (AtmKD/-) is more oncogenic than loss of ATM (Atm-/-) in mouse models, leading to earlier and more frequent lymphomas with Pten deletions. Kinase-dead ATM protein (Atm-KD), but not loss of ATM (Atm-null), prevents replication-dependent removal of Topo-isomerase I-DNA adducts at the step of strand cleavage, leading to severe genomic instability and hypersensitivity to Topo-isomerase I inhibitors. Correspondingly, Topo-isomerase I inhibitors effectively and preferentially eliminate AtmKD/-, but not Atm-proficientor Atm-/- leukemia in animal models. These findings identify ATM kinase-domain missense mutations as a potent oncogenic event and a biomarker for Topo-isomerase I inhibitor based therapy. KW - ATM KW - missense mutation KW - replication fork KW - Topo-isomerase I JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -